CA2078519C - Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3:4,5-bis-0-(1-methylethylidene)-beta-d-fructopyranose and (1-methylcyclohexyl)methanol - Google Patents
Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3:4,5-bis-0-(1-methylethylidene)-beta-d-fructopyranose and (1-methylcyclohexyl)methanol Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
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- C07—ORGANIC CHEMISTRY
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- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
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Abstract
A process for producing chlorosulfate and sulfamate esters of 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose and (1-methylcyclohexyl)methanol is disclosed. The process involves a two step procedure involving in the first step reacting of an alcohol with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran, and in the second step reacting of the resulting intermediate with an amine in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and lower alkanol.
Description
PROCESS FOR THE PREPARATION OF CHLOROSLTLFATE AND
SULFAMATE DERIVATIVES OF 2,3:9,5-BIS-O-(1-MET'HYLETHYLIDENE)-~i-D-FRUCTOPYRANOSE AND (1-METHYLCYCLOHEXYL)METHANOL
This invention is directed to a process for producing chlorosulfate and sulfamate esters of 2,3:4,5-bis-O-(1-methylethylidene)-~i-D-fructopyranose and (1-methylcyclohexyl)methanol. The process in particular involves a two step 1 5 procedure involving in the first step the reaction of an alcohol with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran , and in the second step the reaetion of the resulting intermediate with an amine in a solvent seleeted from the group consisting 2 0 of toluene, t-butyl methyl ether tetrahydrofuran and lower alkanol .
BACKGROUND OF THE INVENTION
Sulfamates of the formula I:
CH20SO~JHRi Rs R ~R3 I
wherein X is O or CH2 and R~, R2, R3, R4, and Rg are as herein defined, are known compounds that have been found to exhibit anticonvulsant 3 0 activity and thus are useful in the treatment of conditions such as epilepsy.
These compounds are disclosed in U.S. Patent Nos. 4,582,916 and 4,513,006, which also disclose processes for production of such compounds.
One reaction scheme disclosed in these prior art patents covers the reaction of an alcohol of the formula RCH20H with a chlorosulfamate of the formula C1S02NH2 or C1S02NHR1 in the presence of a base such as potassium t-butoxide or sodium hydride (NaH) at a temperature of about -20°C to 25°C and in a solvent such as toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), wherein R is a moiety of the formula II:
fts R4 ~3 This process has two major disadvantages. One disadvantage is that it calls for a combination of NaH and DMF which has an uncontrollable exotherm and is therefore potentially explosive. See J. Buckley et al., 1 5 Chemical & Engineering News, July 12, 1982, page 5; and G. DeWail, Chemical & Engineering News, September 13, 1982. Another disadvantage is that the process also uses highly toxic and corrosive chlorosulfonyl isocyanate (CSI) to prepare the commercially unavailable sulfamyl chloride (C1S02NH2). The CSI is not only difficult to work with, because of its toxicity and corrosiveness, 2 0 but also is available from only one commercial supplier.
Another known process disclosed in the above mentioned U.S. Patent No. 4,513,006 for producing the compounds of formula I comprises the reaction of an alcohol of the formula RCH2OH with sulfuryl chloride of the 2 5 formula S02C12 in the presence of a base such as triethylamine or pyridine at a temperature of about -40°C to 25°C in a diethyl ether or methylene chloride solvent to produce a chlorosulfate of the formula RCH20SOZC1. The chlorosulfate of the formula RCH2OS02C1 may then be reacted with an amine of the formula R1NH2 at a temperature of about -40°C to 25°C in a methylene 3 0 chloride or acetonitrile solvent to produce the compound of the formula I.
This process (utilizing diethyl ether, methylene chloride and acetonitrile solvents) produces relatively low yields of the desired end product of formula I in comparison with the process of the present invention.
~Q~~
The final process disclosed in the two patents comprises the reaction of the chlorosulfate of formula RCHZOSOZCI formed as described previously with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile to yield an azidosulfate of the formula RCH20SOZN3.
The azidosulfate is then reduced to a compound of the formula I wherein Rl is hydrogen, by catalytic hydrogenation. T'he disadvantage with this process is that explosions may occur when handling the azide compounds. Also the process contains an additional chemical transformation involving the 1 0 reduction of the azide to the NH2 moiety.
It is an object of the present invention to provide a new and improved process for producing compounds of the formula I, which uses readily available materials, can be carried out under safe conditions and at relatively 1 5 high yields. The advantages of the present invention are described in part below and in part will be obvious from this description and by comparison to the prior art processes described in the Examples section below.
According to the present invention, compounds of the formula I:
CHzOSO2NHR~
Rs 2 5 wherein X is O or CH2 and R1, R2, R3, R~ and Rg are as hereinafter defined are synthesized in two steps by reacting an alcohol of the formula RCH20H, wherein R is a moiety of the formula II:
RS I I
Ra R3 2~'~8~.~ ~
with sulfuryl chloride in a solvent selected from the group consisting of toluene, t-butyl methyl ether (TBME) or tetrahydrofuran (THF), preferably toluene to form a compound of the formula RCH20SOZC1 (formula III), and thereafter in a second step reacting the compound of formula III with an amine of the formula R1NH2 in a solvent selected from the group consisting of THF, TBME, toluene, and lower alkanol (e.g. methanol or ethanol), preferably tetrahydrofuran to produce the compound of formula I:
CH20S~2NHR~
1 C Ra R3 It is to be understood that both the foregoing general and the following detailed description are exemplary and explanatory only and are not intended to be restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to particularly preferred embodiments of the invention. Examples of the preferred embodiments are 2 0 illustrated in the following Examples section.
The novel process of the invention is inherently much safer than the prior art process which employs the potentially explosive combination of NaH/DMF. It also uses sulfuryl chloride and ammonia instead of the highly 2 5 toxic and corrosive chlorosulfonyl isocyanate (CSI). Further the sulfuryl chloride is more commercially accessible and much less costly than CSI.
Moreover, the process results in relatively high yields of about 85% to 97°l0, as compared with the prior art processes which have yields in the range of from about 1 °!o to 60°l0. The apparent reason for the high yields are the particularly 3 0 selected solvents chosen for each step of the reaction sequence. The combination of the use of inexpensive and readily accessible sulfuryl chloride and the higher yields results in a much more economical and/or safer process when compared to the prior art processes.
~~1~~~~
More particularly, the present invention is directed to a process for synthesizing compounds of the formula I:
CHZOSOzNHR~
wherein X is CH2 or O;
Rl is hydrogen or Cl-C4 alkyl; and R2, R3, ~ and Rg are independently hydrogen or alkyl, and, when X is O, R2 and R3 and/or R4 and R5, together, may be a methylenedioxy group of 1 0 the following formula IV:
Fts~C
iv R ~ ~O
wherein Rg and R~ are the same or different and are hydrogen, alkyl or 1 5 are both alkyl and joined to form a cyclopentyl or cyelohexyl ring, with the proviso that Rb and R~ may not both be hydrogen at the same time.
R~, in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and isopropyl. Alkyl groups for R2, R3, R4, Rg, R~, and R~ are of 2 0 1 to 3 carbons and include methyl, ethyl, isopropyl and n-propyl. Alkyl throughout this specification includes straight and branched chain alkyl groups.
This process is particularly useful for producing compounds of the 2 5 formula I wherein X is oxygen and both R2 and R3, and R4 and Rg together are methylenedioxy groups of the formula IV, wherein R~ an R~ are both alkyl.
The process comprises reacting an alcohol of the formula RCH20H
with sulfuryl chloride of the formula S02C12 in the presence of a tertiary or 3 0 heterocyclic amine base such as pyridine, pyridine derivatives or triethylamine, preferably pyridine at a temperature of about -78°C to 40°C, more preferably at a temperature of about 0°C to 40°C in a solvent such as toluene, t-butyl methyl ether (TBME), or tetrahydrofuran (THF), preferably toluene, to produce a chlorosulfate of the formula III, i.e. RCH20S02C1, wherein R is a moiety of the formula II:
1 0 The chlorosulfate of the formula III RCH20S02C1 is then reacted with an amine of the formula R1NH2 at a temperature of about -50°C to 50°C, more preferably of about 15°C to 20°C in a solvent such as THF, TBME, toluene, methanol or ethanol, preferably THF to produce a compound of formula I.
1 5 The reaction with the amine of the formula RlNHz can be carried out using any appropriate amine source, preferably ammonia gas (R1=H) from an ammonia gas generating source such as aqueous or anhydrous ammonia under pressure of from about atmospheric to 50 psi, more preferably at about 20-30 psi, or the amine can be bubbled into the reaction solution. The reaction 2 0 can also be carried out using a pre-saturated solution of ammonia in THF.
To obtain a purer product the compound of formula I may be recrystallized by conventional techniques such as from ethanol/water or ethyl acetate/hexane.
The starting materials of the formula RCH20H may be obtained commercially from Aldrich Chemical Corporation or synthesized by techniques well known in the art. For example, starting materials of the formula RCH20H, wherein R2, R3, R4 and Rg are methylenedioxy groups of 3 0 the formula IV may be obtained by the method of R. F. Brady in "Carbohydrate Research", Vol. 15, p. 35 to 40 (1970) or by reaction of the trimethylsilyl enol ether of a It~,COR~ ketone or aldehyde with fructose at a temperature of about 25°C in a solvent such as an alkyl halide, e.g.
methylene chloride in the presence of a erotic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride. The trimethylsilyl enol ether reaction is described by G. L. Larson et al in J. Org. Chem. Vol. 38, No. 22, p. 3935 (1973).
A particularly preferred process according to the present invention comprises reacting a compound of the formula V:
CH3 O'... ,'' C>
a~ O~~.CH3 V
with sulfuryl chloride of the formula S02C12 in the presence of an amine base such as pyridine and in toluene at a temperature of .about 0°C to 40°C and a pressure of about atmospheric to produce a compound of the formula VI:
O CH20SOzCl CH3 O'." '', O
~O' O~CH3 VI
The compound of formula VI is thereafter reacted with ammonia at a pressure of ca. 30 psi in THF at a temperature of about 15 to 20°C to produce 2 0 the compound of the formula VII:
O CHZOSOzNHz 0... ' CH3 ' O
~O, O~CH3 VII
The same process can be used to make the L-fructopyranose derived 2 5 enantiomer instead of the D-fructopyranose enantiomer of formula VII by using the L-enantiomer starting material instead of the D-enantiomer starting material of formula V.
The invention will now be illustrated by examples. The examples axe not intended to be limiting of the scope of the present invention but read in conjunction with the detailed and general description above, provide further understanding of the present invention and outline a method of practicing the process of the invention.
EXAMPLES
1 0 Examples 1 and 2 show the production of intermediates according to the present invention. Example 3-5 and 14 are examples of the production of the final desired products by the two step process of the invention, Examples 6-13 are prior art comparative examples. Table 1 compares the yields of the prior art processes of examples 6-10 with the yields of the two step processes of 1 5 the present invention (Examples 3-5) for producing the compound of formula VII.
Table 2 compares the yields of the process of the present invention (Example 14) with the yields of prior art processes (Examples 11-13) for 2 0 producing (1-methylcyclohexyl)methane sulfamate. As is apparent from the Tables 1 and 2 the process of the present invention results in yields of final product greatly in excess of the yields of the prior art processes and superior purity of the final product.
TablQ 1 z SOZCIz " .
p"' --.-~ O", ~ O
H3C~ CH3 pyridine H3C~ CH3 ~Ci~ ~ solv~nt 1 / 'O
H3C CH3 HsC CH3 V VI
CHZOSOzNHz NH3 O,.
---s. HsC~ . ~CHa solvent 2 O
H3C CHs Process solvent NH3 Phys. Purity Yield#
1 Descript (%) solvent (VII) (VII) (VII) 1 0 Ex. tolueneTHF 30 psi wh. solid99.70 93.50 Ex. 4 tolueneTHF bubbling wh. solid96.20 87.20 Ex. 5 tolueneTHF saturationwh. solid- 83.30"
Ex.6 CH2CI2CH2CI2 bubbling bl.tar 15.10 36.83 Ex.7 CH2C12CH3CN bubbling bl.tar 25.80 60.40 Ex.8 etherCH2CI2 bubbling bl.tar 14.80 32.43 Ex.9 etherCH3CN bubbling bl.tar 18.70 41.91 Ex. 10 etherCH2C12 pressure bl.tar 0.55 1.08 2 0 #Yield sed purity LC analysis.
ba on by G
')soiated crudeyield.
Table 2 ~CHZOH S02CIz i-y ,CHzOS02C1N~ CH20SOzNHz (~~(~CH3 s ( w" ~CH
~~CH
pyridine ~/ 3 s solvent 1 solvent Process solvent solventNH3 Phys. Purity (% ) 1 2 Descript Yield#
Ex. 11 CH2C12 CH3CN bubbling bl.tar 2.24 1.34 Ex. 12 ether CH3CN bubbling bl.tar 0.00 0.00 Ex. 13 CH2CI2 CH2CI2 bubbling bl.tar 29.10 23.97 3 5 Ex. 14 tolueneTHF 28 psi yel.oil 95.00 -81.33 # Yieid based GLC analysis.
on purity by MCN~5i6 ,o Example 1 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(i-D-fructopyranose Under nitrogen, acetone (144.0 L, 113.0 kg, 1946 mol) was cooled to 0°-10°C. With stirring, concentrated sulfuric acid (7.2 L, 13.2 kg, 135.6 mol) was added gradually (approx. 0.5 h) so that the temperature did not exceed 20°C
(jacket temperature at -15°C). External cooling was discontinued and D-fructose (12.0 kg, 66.6 mol) was added gradually (in 2.0 kg portions) over 2 h 1 0 while maintaining the temperature between 8-15°C. The suspension was stirred at room temperature for an additional 2-3 h after all the fructose had dissolved. The solution was then cooled to 5°C and 50% sodium hydroxide (24.0 kg, 297.6 mol) was added at a rate so as to maintain the solution temperature below 20°C (addition was complete in 1 h with a jacket 1 5 temperature at -I5°C). The resulting slurry was centrifuged to remove the precipitated salt (sodium sulfate). Solvent was removed from the filtrate by vacuum distillation and the residual oil was stored at room temperature.
The semi-solid reaction product was dissolved in t-butyl methyl ether (48.8 kg, 66.4L). The solution was washed with distilled water (2 x 9.0 L) and 2 0 concentrated to give an oil. The oil was dissolved in hexane (24.0 L)/isopropanol (3.5 L) with gradual warming to 60°C. The product crystallized with cooling. The solid was collected by centrifugation and dried in a vacuum oven at 38°C for 8.0 h to give 10.8 kg (62.4% yield, 100.8%
purity by GLC) of a white solid, mp 95-96°C.
Example 2 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-ji-D-fructopyranose sulfonyl chloride (chlorosulfate) A solution of sulfuryl chloride (486.9 g, 3.60 mol) and toluene (4.0 L) 3 0 was cooled to -I4°C. A solution of the alcohol of Example 1 (782.4 g, 3.00 mol) and pyridine (285.3 g, 3.60 mol) in toluene (4.0 L) was added to the cooled sulfuryl chloride solution. The rate of addition was regulated so that the reaction temperature was maintained between -IO° to 5°C
(required I.5 h). A
white solid precipitated from the reaction immediately. After the addition 3 5 was complete, the cooling bath was removed and the mixture stirred for 2.0 h.
i~
The reaction mixture was diluted with distilled water (4.0 L) and the resultant layers separated. The organic layer was then washed sequentially with a 10%
citric acid solution (2.6 L), distilled water (2.6 L), a saturated sodium bicarbonate solution (2.6 L), and a saturated sodium chloride solution (2.6 L).
Removal of the solvent by vacuum disdl:lation (in a 45°C bath at <5 mm) afforded chlorosulfate (1101g, 102.2%) as an almost colorless oil. The product was found to be 98.3% pure (wt% by GLC) giving a corrected yield of 100.5%.
1 0 Example 3 - Preparation of 2,3:4,5-bis-U-(1-methylethylidene) (3-D-fructopyranose sulfamate (ammonolysis at 30 psi) Chlorosulfate (1076.4 g, 3.0 mol) of Example 2 in tetrahydrofuran (8.0 L) cvas added to a 12.0 L stainless steel autoclave. The autoclave was then 1 5 pressurized with anhydrous ammonia to 30 psi and stirred (400 rpm) at ambient temperature for 24.0 h. A mild exotherm was noticed after 2.0 h (25 to 38°C). The autoclave was depressurized by venting to the air. The light yellow solution, containing a white granular solid, was filtered and the filter cake washed with tetrahydrofuran (400 mL). The tetrahydrofuran was 2 0 removed in. vacuo (50°C, house vac) to afford the product as a light yellow oil (1110.0 g, 109.0%). The oil was slurried in n-hexane (2.1 L) and warmed on a steam bath for 0.5 h. The oil changed to a white paste and then crystallized.
After cooling to room temperature, the title compound was collected by filtration and air dried for 24.0 h (955.1 g, 93.8% yield and 99.7% pure by GLC
2 5 giving a corrected yield of 93.5%).
A sample (900 g) was recrystallized from 95% ethanol (900 mL) with the addition of distilled water (1800 mL) and the pH adjusted to 8-8.5 by adding 50% NaOH (3.5 mL). The solid was collected by vacuum filtration and air 3 0 dried (72.0 h) to yield the title compound (828.0 g, 92.0% isolated yield, 100.1 %
pure by GLC) as a white solid, mp 123-124°C.
~~~~~3~~
Example 4 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene) ~i-D-fructopyranose sulfamate (ammonolysis by bubbling ammonia gas) Into a 500 mL, four-neck round bottom flask equipped with an overhead stirrer, bubbler, thermometer, and inlet tube was placed 19.90.8 (0.0556 mol) of the chlorosulfate of Example 2 which was dissolved in 200 mL
of tetrahydrofuran. Anhydrous ammonia was bubbled into the solution at 1 0 room temperature for about 5 h. The reaction mixture was filtered to remove the precipitate and the solvent removed in vacuo. The oil was slurried in hexane (50 mL) with warming on a steam bath until it became pasty white.
The oil crystallized with stirring on cooling to room temperature. The mixture was left to stand at room temperature overnight. 'fhe mixture was 1 5 then filtered, washed with hexane, and air dried to give the title compound as a white solid (17.11 g, 96.2% pure by GLC, 87.2% yield).
Example 5 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~i-D-fructopyranose sulfamate (saturation ammonolysis) Anhydrous ammonia was added to 490 kg of THF until a pressure of 22 psi was reached. While maintaining a pressure of 22 psi, a solution of the chlorosulfate (303 kg, 845 mol) prepared as in example 2, and dissolved in 415 kg of THF was pumped into the presaturated NH3/THF solution over a 2 h 2 5 period while maintaining an internal temperature of 15-20°C. After 3 h the excess ammonia was vented and the reaction mixture filtered. The THF
solution was concentrated in vacuo to a syrup, diluted with isopropanol (185 kg), and concentrated again. The resultant residue was dissolved in a solution of isopropanol (150 kg) and petroleum spirits (370 kg) containing 8.0 3 0 kg of activated charcoal and warmed to 80°C for 30 min. The warm solution was filtered to remove charcoal and cooled. After cooling to 0-5°C, the title compound was collected by filtration and dried under vacuum at 45°C
(239 kg, 83.3% yield).
Example 6 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(3-D-fructopyranose sulfamate Under nitrogen, a solution of the alcohol of Example 1 (15.0 g, 0.0576 mop and pyridine (15 mL, 0.18 mot) in methylene chloride (60 mL) was cooled to -40°C in a dry ice/isopropanol bath. With stirring, a solution of sulfuryl chloride (16.0 g, 0.118 moD in mekhylene chloride (10 mL) was added gradually (approx, 50 minutes) so that the temperature did not exceed -25°C.
1 0 The ice bath was removed as soon as the addition was complete and the reaction mixture stirred for an additional 2 h. During this time the light yellow precipitate became a clumpy brown solid. Solvent was removed In vucuo to yield a sticky, brown residue. The residue was dissolved in 100 mL
methylene chloride and anhydrous ammonia was bubbled through the 1 5 mixture overnight at ambient temperature. The dark reaction mixture was concentrated in vacuo to give 47.7 g of the title compound as a black residue.
The crude product was found to be 15.10% pure by GLC giving a corrected yield of 36.83%.
2 0 Example 7 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except acetonitrile was used instead of methylene chloride. The title compound was 2 5 isolated as a black residue (45.77 g). The crude product was found to be 25.8%
pure by GLC giving a corrected yield of 60.40%.
Example 8 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-f3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except ether was used instead of methylene chloride in the first step. The title compound was isolated as a black residue (42.84 g). The crude product was found to be 14.8%
pure by GLC giving a corrected yield of 32.43%.
'1 4 ~~~~~a~
Example 9 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except ether was used instead of solvent I (methylene chloride) and acetonitrile was used instead of methylene chloride for solvent 2 (see Table I). A black residue (43.82 g) was obtained on work-up. The crude product was found to be 18.70%
pure by GLC giving a corrected yield of 41.91 %.
Example 10 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 8 except that the 1 5 chlorosulfate/methylene chloride solution was placed in a pear shaped pressure bottle and cooled in a dry iee/isopropanol bath. Anhydrous ammonia was bubbled through the mixture for approximately 30~minutes;
then the bottle was tightly stoppered and allowed to slowly warm to room temperature overnight. The bottle was cooled back down before opening and 2 0 the mixture concentrated in vacuo to give 38.51 g of the title compound as a brown tar. The crude product was found to be only 0.55% pure by GLC giving a corrected yield of 1.08%.
Example 11 - (Comparative Example) Preparation of 25 (1-methylcyclohexyl)methane sulfamate Under nitrogen, a solution of (1-methylcyclohexyl)methanol (7.4 g, 0.057 mol) and pyridine (15 mL, 0.179 mol) in methylene chloride (100 mL) was cooled to -10°C in a ice/methanol bath. With stirring, a solution of 3 0 sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (20 mL) was added gradually (approx. 1.0 h) so that the temperature did not exceed -5°C.
The ice bath was removed and the light yellow solution allowed to slowly warm to room temperature over a 2.0 h period. Solvent was removed in vacuo and the resulting yellow slush was slurried in acetonitrile (140 mL). Anhydrous 3 5 ammonia was bubbled through the mixture for 4.0 h. The mixture was filtered, washed with fresh acetonitrile, and concentrated in vacuo to give the ,5 title compound (7.12 g) as a dark oil. The crude product was found to be only 2.24% pure by GLC giving a corrected yield of 1.34%.
Example 12 - (Comparative Example) Preparation of (1-methylcyclohexyl)methane~ sulfamate The reaction was carried out the same as that in Example 11 except diethylether was used for methylene chloride as solvent 1. (see Table 2). No 1 0 product was isolated based on GLC analysis.
Example 13 - (Comparative Example) Preparation of (1-methylcyclohexyl)methane sulfamate 1 5 The reaction was carried out the same as that in Example 11 except methylene chloride was used instead of acetonitrile as solvent 2 (see Table 2).
A product (9.85 g) was isolated as a dark oil. The crude product was found to be 29.1 % pure by GLC giving a corrected yield of 23.97%.
2 0 Example 14 - Preparation of (1-methylcyclohexyl)methane sulfamate Under argon, sulfuryl chloride (18.67 g, 0.138 mol) in toluene (150 mL) was cooled to -50°C in a dry ice/acetone bath. With stirring, a solution of 1-methyl-1-cyclohexane methanol (14.74 g, 0.115 mol) and pyridine (10.94 g, 2 5 0.138 mol) in toluene (150 mL) was added gradually (approx. 40-50 minutes) so that the temperature did not exceed -45°C. The ice bath was removed as soon as the addition was complete. After stirring for an additional 30 minutes water (300 mL) was added and the layers separated. The organic layer was washed with 10% citric acid (2 x 60 mL), water (2 x 100 mL), saturated sodium 3 0 bicarbonate (1 x 100 mL), and saturated sodium chloride (1 x 200 mL), then dried over solid sodium sulfate, filtered, and concentrated in vacuo to give the chlorosulfate (23.53 g, 90.6% yield) as a brownish yellow oil. The oil was dissolved in tetrahydrofuran (300 mL) and the solution added to a 1.0 L
autoclave (with glass liner). The autoclave was pressurized with anhydrous 3 5 ammonia to 28 psi and stirred (290 rpm) at ambient temperature for 16 h. A
mild exotherm was noticed after I.0 h (22 - 35°C). The autoclave was ~0'~8~~.~
depressurized by venting to the air. The mixture was filtered and the solvent removed in vacuo to give 20.41 g of the title compound as a yellow oil. The product was found to be 95.0% pure by GLC giving a corrected yield of 81.33%.
A comparison of the examples of the present invention (Exs. 3-5 and 14) versus those comparative examples of the prior art (Exs. 6-13) in Tables 1 and 2 evidences the advantages of the use o:f the particularly selected solvents in the process of the present invention to produce surprisingly superior 1 0 results over the prior art processes. A direct comparison of Ex. 4 of the invention utilizing the preferred solvents of the invention, e.g. toluene and TI-1F versus comparitive Exs. 6-9 in Table 1 shows a yield improvement of at least 40% and a significant purity improvement for the final product 2,3:4,5-bis-O-(1-methylethylidene)-ø-D-fructopyranose sulfamate . Analagous 1 5 process result improvements are illustrated in Table 2 for the preparation of (I-methylcyclohexyl)methane sulfamate The scope of the present invention is not limited by the description, examples and suggested uses described herein and modifications can be made 2 0 without departing from the spirit of the invention. For example, other sulfamates may be produced utilizing the process of the invention beyond those exemplefied herein.
Applications of the process and methods of the present invention can 2 5 be accomplished by any synthetic method and technique as is presently or prospectively known to those skilled in the chemical and pharmaceutical process arts. Thus it is intended that the present invention cover any modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
SULFAMATE DERIVATIVES OF 2,3:9,5-BIS-O-(1-MET'HYLETHYLIDENE)-~i-D-FRUCTOPYRANOSE AND (1-METHYLCYCLOHEXYL)METHANOL
This invention is directed to a process for producing chlorosulfate and sulfamate esters of 2,3:4,5-bis-O-(1-methylethylidene)-~i-D-fructopyranose and (1-methylcyclohexyl)methanol. The process in particular involves a two step 1 5 procedure involving in the first step the reaction of an alcohol with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran , and in the second step the reaetion of the resulting intermediate with an amine in a solvent seleeted from the group consisting 2 0 of toluene, t-butyl methyl ether tetrahydrofuran and lower alkanol .
BACKGROUND OF THE INVENTION
Sulfamates of the formula I:
CH20SO~JHRi Rs R ~R3 I
wherein X is O or CH2 and R~, R2, R3, R4, and Rg are as herein defined, are known compounds that have been found to exhibit anticonvulsant 3 0 activity and thus are useful in the treatment of conditions such as epilepsy.
These compounds are disclosed in U.S. Patent Nos. 4,582,916 and 4,513,006, which also disclose processes for production of such compounds.
One reaction scheme disclosed in these prior art patents covers the reaction of an alcohol of the formula RCH20H with a chlorosulfamate of the formula C1S02NH2 or C1S02NHR1 in the presence of a base such as potassium t-butoxide or sodium hydride (NaH) at a temperature of about -20°C to 25°C and in a solvent such as toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), wherein R is a moiety of the formula II:
fts R4 ~3 This process has two major disadvantages. One disadvantage is that it calls for a combination of NaH and DMF which has an uncontrollable exotherm and is therefore potentially explosive. See J. Buckley et al., 1 5 Chemical & Engineering News, July 12, 1982, page 5; and G. DeWail, Chemical & Engineering News, September 13, 1982. Another disadvantage is that the process also uses highly toxic and corrosive chlorosulfonyl isocyanate (CSI) to prepare the commercially unavailable sulfamyl chloride (C1S02NH2). The CSI is not only difficult to work with, because of its toxicity and corrosiveness, 2 0 but also is available from only one commercial supplier.
Another known process disclosed in the above mentioned U.S. Patent No. 4,513,006 for producing the compounds of formula I comprises the reaction of an alcohol of the formula RCH2OH with sulfuryl chloride of the 2 5 formula S02C12 in the presence of a base such as triethylamine or pyridine at a temperature of about -40°C to 25°C in a diethyl ether or methylene chloride solvent to produce a chlorosulfate of the formula RCH20SOZC1. The chlorosulfate of the formula RCH2OS02C1 may then be reacted with an amine of the formula R1NH2 at a temperature of about -40°C to 25°C in a methylene 3 0 chloride or acetonitrile solvent to produce the compound of the formula I.
This process (utilizing diethyl ether, methylene chloride and acetonitrile solvents) produces relatively low yields of the desired end product of formula I in comparison with the process of the present invention.
~Q~~
The final process disclosed in the two patents comprises the reaction of the chlorosulfate of formula RCHZOSOZCI formed as described previously with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile to yield an azidosulfate of the formula RCH20SOZN3.
The azidosulfate is then reduced to a compound of the formula I wherein Rl is hydrogen, by catalytic hydrogenation. T'he disadvantage with this process is that explosions may occur when handling the azide compounds. Also the process contains an additional chemical transformation involving the 1 0 reduction of the azide to the NH2 moiety.
It is an object of the present invention to provide a new and improved process for producing compounds of the formula I, which uses readily available materials, can be carried out under safe conditions and at relatively 1 5 high yields. The advantages of the present invention are described in part below and in part will be obvious from this description and by comparison to the prior art processes described in the Examples section below.
According to the present invention, compounds of the formula I:
CHzOSO2NHR~
Rs 2 5 wherein X is O or CH2 and R1, R2, R3, R~ and Rg are as hereinafter defined are synthesized in two steps by reacting an alcohol of the formula RCH20H, wherein R is a moiety of the formula II:
RS I I
Ra R3 2~'~8~.~ ~
with sulfuryl chloride in a solvent selected from the group consisting of toluene, t-butyl methyl ether (TBME) or tetrahydrofuran (THF), preferably toluene to form a compound of the formula RCH20SOZC1 (formula III), and thereafter in a second step reacting the compound of formula III with an amine of the formula R1NH2 in a solvent selected from the group consisting of THF, TBME, toluene, and lower alkanol (e.g. methanol or ethanol), preferably tetrahydrofuran to produce the compound of formula I:
CH20S~2NHR~
1 C Ra R3 It is to be understood that both the foregoing general and the following detailed description are exemplary and explanatory only and are not intended to be restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to particularly preferred embodiments of the invention. Examples of the preferred embodiments are 2 0 illustrated in the following Examples section.
The novel process of the invention is inherently much safer than the prior art process which employs the potentially explosive combination of NaH/DMF. It also uses sulfuryl chloride and ammonia instead of the highly 2 5 toxic and corrosive chlorosulfonyl isocyanate (CSI). Further the sulfuryl chloride is more commercially accessible and much less costly than CSI.
Moreover, the process results in relatively high yields of about 85% to 97°l0, as compared with the prior art processes which have yields in the range of from about 1 °!o to 60°l0. The apparent reason for the high yields are the particularly 3 0 selected solvents chosen for each step of the reaction sequence. The combination of the use of inexpensive and readily accessible sulfuryl chloride and the higher yields results in a much more economical and/or safer process when compared to the prior art processes.
~~1~~~~
More particularly, the present invention is directed to a process for synthesizing compounds of the formula I:
CHZOSOzNHR~
wherein X is CH2 or O;
Rl is hydrogen or Cl-C4 alkyl; and R2, R3, ~ and Rg are independently hydrogen or alkyl, and, when X is O, R2 and R3 and/or R4 and R5, together, may be a methylenedioxy group of 1 0 the following formula IV:
Fts~C
iv R ~ ~O
wherein Rg and R~ are the same or different and are hydrogen, alkyl or 1 5 are both alkyl and joined to form a cyclopentyl or cyelohexyl ring, with the proviso that Rb and R~ may not both be hydrogen at the same time.
R~, in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and isopropyl. Alkyl groups for R2, R3, R4, Rg, R~, and R~ are of 2 0 1 to 3 carbons and include methyl, ethyl, isopropyl and n-propyl. Alkyl throughout this specification includes straight and branched chain alkyl groups.
This process is particularly useful for producing compounds of the 2 5 formula I wherein X is oxygen and both R2 and R3, and R4 and Rg together are methylenedioxy groups of the formula IV, wherein R~ an R~ are both alkyl.
The process comprises reacting an alcohol of the formula RCH20H
with sulfuryl chloride of the formula S02C12 in the presence of a tertiary or 3 0 heterocyclic amine base such as pyridine, pyridine derivatives or triethylamine, preferably pyridine at a temperature of about -78°C to 40°C, more preferably at a temperature of about 0°C to 40°C in a solvent such as toluene, t-butyl methyl ether (TBME), or tetrahydrofuran (THF), preferably toluene, to produce a chlorosulfate of the formula III, i.e. RCH20S02C1, wherein R is a moiety of the formula II:
1 0 The chlorosulfate of the formula III RCH20S02C1 is then reacted with an amine of the formula R1NH2 at a temperature of about -50°C to 50°C, more preferably of about 15°C to 20°C in a solvent such as THF, TBME, toluene, methanol or ethanol, preferably THF to produce a compound of formula I.
1 5 The reaction with the amine of the formula RlNHz can be carried out using any appropriate amine source, preferably ammonia gas (R1=H) from an ammonia gas generating source such as aqueous or anhydrous ammonia under pressure of from about atmospheric to 50 psi, more preferably at about 20-30 psi, or the amine can be bubbled into the reaction solution. The reaction 2 0 can also be carried out using a pre-saturated solution of ammonia in THF.
To obtain a purer product the compound of formula I may be recrystallized by conventional techniques such as from ethanol/water or ethyl acetate/hexane.
The starting materials of the formula RCH20H may be obtained commercially from Aldrich Chemical Corporation or synthesized by techniques well known in the art. For example, starting materials of the formula RCH20H, wherein R2, R3, R4 and Rg are methylenedioxy groups of 3 0 the formula IV may be obtained by the method of R. F. Brady in "Carbohydrate Research", Vol. 15, p. 35 to 40 (1970) or by reaction of the trimethylsilyl enol ether of a It~,COR~ ketone or aldehyde with fructose at a temperature of about 25°C in a solvent such as an alkyl halide, e.g.
methylene chloride in the presence of a erotic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride. The trimethylsilyl enol ether reaction is described by G. L. Larson et al in J. Org. Chem. Vol. 38, No. 22, p. 3935 (1973).
A particularly preferred process according to the present invention comprises reacting a compound of the formula V:
CH3 O'... ,'' C>
a~ O~~.CH3 V
with sulfuryl chloride of the formula S02C12 in the presence of an amine base such as pyridine and in toluene at a temperature of .about 0°C to 40°C and a pressure of about atmospheric to produce a compound of the formula VI:
O CH20SOzCl CH3 O'." '', O
~O' O~CH3 VI
The compound of formula VI is thereafter reacted with ammonia at a pressure of ca. 30 psi in THF at a temperature of about 15 to 20°C to produce 2 0 the compound of the formula VII:
O CHZOSOzNHz 0... ' CH3 ' O
~O, O~CH3 VII
The same process can be used to make the L-fructopyranose derived 2 5 enantiomer instead of the D-fructopyranose enantiomer of formula VII by using the L-enantiomer starting material instead of the D-enantiomer starting material of formula V.
The invention will now be illustrated by examples. The examples axe not intended to be limiting of the scope of the present invention but read in conjunction with the detailed and general description above, provide further understanding of the present invention and outline a method of practicing the process of the invention.
EXAMPLES
1 0 Examples 1 and 2 show the production of intermediates according to the present invention. Example 3-5 and 14 are examples of the production of the final desired products by the two step process of the invention, Examples 6-13 are prior art comparative examples. Table 1 compares the yields of the prior art processes of examples 6-10 with the yields of the two step processes of 1 5 the present invention (Examples 3-5) for producing the compound of formula VII.
Table 2 compares the yields of the process of the present invention (Example 14) with the yields of prior art processes (Examples 11-13) for 2 0 producing (1-methylcyclohexyl)methane sulfamate. As is apparent from the Tables 1 and 2 the process of the present invention results in yields of final product greatly in excess of the yields of the prior art processes and superior purity of the final product.
TablQ 1 z SOZCIz " .
p"' --.-~ O", ~ O
H3C~ CH3 pyridine H3C~ CH3 ~Ci~ ~ solv~nt 1 / 'O
H3C CH3 HsC CH3 V VI
CHZOSOzNHz NH3 O,.
---s. HsC~ . ~CHa solvent 2 O
H3C CHs Process solvent NH3 Phys. Purity Yield#
1 Descript (%) solvent (VII) (VII) (VII) 1 0 Ex. tolueneTHF 30 psi wh. solid99.70 93.50 Ex. 4 tolueneTHF bubbling wh. solid96.20 87.20 Ex. 5 tolueneTHF saturationwh. solid- 83.30"
Ex.6 CH2CI2CH2CI2 bubbling bl.tar 15.10 36.83 Ex.7 CH2C12CH3CN bubbling bl.tar 25.80 60.40 Ex.8 etherCH2CI2 bubbling bl.tar 14.80 32.43 Ex.9 etherCH3CN bubbling bl.tar 18.70 41.91 Ex. 10 etherCH2C12 pressure bl.tar 0.55 1.08 2 0 #Yield sed purity LC analysis.
ba on by G
')soiated crudeyield.
Table 2 ~CHZOH S02CIz i-y ,CHzOS02C1N~ CH20SOzNHz (~~(~CH3 s ( w" ~CH
~~CH
pyridine ~/ 3 s solvent 1 solvent Process solvent solventNH3 Phys. Purity (% ) 1 2 Descript Yield#
Ex. 11 CH2C12 CH3CN bubbling bl.tar 2.24 1.34 Ex. 12 ether CH3CN bubbling bl.tar 0.00 0.00 Ex. 13 CH2CI2 CH2CI2 bubbling bl.tar 29.10 23.97 3 5 Ex. 14 tolueneTHF 28 psi yel.oil 95.00 -81.33 # Yieid based GLC analysis.
on purity by MCN~5i6 ,o Example 1 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(i-D-fructopyranose Under nitrogen, acetone (144.0 L, 113.0 kg, 1946 mol) was cooled to 0°-10°C. With stirring, concentrated sulfuric acid (7.2 L, 13.2 kg, 135.6 mol) was added gradually (approx. 0.5 h) so that the temperature did not exceed 20°C
(jacket temperature at -15°C). External cooling was discontinued and D-fructose (12.0 kg, 66.6 mol) was added gradually (in 2.0 kg portions) over 2 h 1 0 while maintaining the temperature between 8-15°C. The suspension was stirred at room temperature for an additional 2-3 h after all the fructose had dissolved. The solution was then cooled to 5°C and 50% sodium hydroxide (24.0 kg, 297.6 mol) was added at a rate so as to maintain the solution temperature below 20°C (addition was complete in 1 h with a jacket 1 5 temperature at -I5°C). The resulting slurry was centrifuged to remove the precipitated salt (sodium sulfate). Solvent was removed from the filtrate by vacuum distillation and the residual oil was stored at room temperature.
The semi-solid reaction product was dissolved in t-butyl methyl ether (48.8 kg, 66.4L). The solution was washed with distilled water (2 x 9.0 L) and 2 0 concentrated to give an oil. The oil was dissolved in hexane (24.0 L)/isopropanol (3.5 L) with gradual warming to 60°C. The product crystallized with cooling. The solid was collected by centrifugation and dried in a vacuum oven at 38°C for 8.0 h to give 10.8 kg (62.4% yield, 100.8%
purity by GLC) of a white solid, mp 95-96°C.
Example 2 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-ji-D-fructopyranose sulfonyl chloride (chlorosulfate) A solution of sulfuryl chloride (486.9 g, 3.60 mol) and toluene (4.0 L) 3 0 was cooled to -I4°C. A solution of the alcohol of Example 1 (782.4 g, 3.00 mol) and pyridine (285.3 g, 3.60 mol) in toluene (4.0 L) was added to the cooled sulfuryl chloride solution. The rate of addition was regulated so that the reaction temperature was maintained between -IO° to 5°C
(required I.5 h). A
white solid precipitated from the reaction immediately. After the addition 3 5 was complete, the cooling bath was removed and the mixture stirred for 2.0 h.
i~
The reaction mixture was diluted with distilled water (4.0 L) and the resultant layers separated. The organic layer was then washed sequentially with a 10%
citric acid solution (2.6 L), distilled water (2.6 L), a saturated sodium bicarbonate solution (2.6 L), and a saturated sodium chloride solution (2.6 L).
Removal of the solvent by vacuum disdl:lation (in a 45°C bath at <5 mm) afforded chlorosulfate (1101g, 102.2%) as an almost colorless oil. The product was found to be 98.3% pure (wt% by GLC) giving a corrected yield of 100.5%.
1 0 Example 3 - Preparation of 2,3:4,5-bis-U-(1-methylethylidene) (3-D-fructopyranose sulfamate (ammonolysis at 30 psi) Chlorosulfate (1076.4 g, 3.0 mol) of Example 2 in tetrahydrofuran (8.0 L) cvas added to a 12.0 L stainless steel autoclave. The autoclave was then 1 5 pressurized with anhydrous ammonia to 30 psi and stirred (400 rpm) at ambient temperature for 24.0 h. A mild exotherm was noticed after 2.0 h (25 to 38°C). The autoclave was depressurized by venting to the air. The light yellow solution, containing a white granular solid, was filtered and the filter cake washed with tetrahydrofuran (400 mL). The tetrahydrofuran was 2 0 removed in. vacuo (50°C, house vac) to afford the product as a light yellow oil (1110.0 g, 109.0%). The oil was slurried in n-hexane (2.1 L) and warmed on a steam bath for 0.5 h. The oil changed to a white paste and then crystallized.
After cooling to room temperature, the title compound was collected by filtration and air dried for 24.0 h (955.1 g, 93.8% yield and 99.7% pure by GLC
2 5 giving a corrected yield of 93.5%).
A sample (900 g) was recrystallized from 95% ethanol (900 mL) with the addition of distilled water (1800 mL) and the pH adjusted to 8-8.5 by adding 50% NaOH (3.5 mL). The solid was collected by vacuum filtration and air 3 0 dried (72.0 h) to yield the title compound (828.0 g, 92.0% isolated yield, 100.1 %
pure by GLC) as a white solid, mp 123-124°C.
~~~~~3~~
Example 4 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene) ~i-D-fructopyranose sulfamate (ammonolysis by bubbling ammonia gas) Into a 500 mL, four-neck round bottom flask equipped with an overhead stirrer, bubbler, thermometer, and inlet tube was placed 19.90.8 (0.0556 mol) of the chlorosulfate of Example 2 which was dissolved in 200 mL
of tetrahydrofuran. Anhydrous ammonia was bubbled into the solution at 1 0 room temperature for about 5 h. The reaction mixture was filtered to remove the precipitate and the solvent removed in vacuo. The oil was slurried in hexane (50 mL) with warming on a steam bath until it became pasty white.
The oil crystallized with stirring on cooling to room temperature. The mixture was left to stand at room temperature overnight. 'fhe mixture was 1 5 then filtered, washed with hexane, and air dried to give the title compound as a white solid (17.11 g, 96.2% pure by GLC, 87.2% yield).
Example 5 - Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~i-D-fructopyranose sulfamate (saturation ammonolysis) Anhydrous ammonia was added to 490 kg of THF until a pressure of 22 psi was reached. While maintaining a pressure of 22 psi, a solution of the chlorosulfate (303 kg, 845 mol) prepared as in example 2, and dissolved in 415 kg of THF was pumped into the presaturated NH3/THF solution over a 2 h 2 5 period while maintaining an internal temperature of 15-20°C. After 3 h the excess ammonia was vented and the reaction mixture filtered. The THF
solution was concentrated in vacuo to a syrup, diluted with isopropanol (185 kg), and concentrated again. The resultant residue was dissolved in a solution of isopropanol (150 kg) and petroleum spirits (370 kg) containing 8.0 3 0 kg of activated charcoal and warmed to 80°C for 30 min. The warm solution was filtered to remove charcoal and cooled. After cooling to 0-5°C, the title compound was collected by filtration and dried under vacuum at 45°C
(239 kg, 83.3% yield).
Example 6 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(3-D-fructopyranose sulfamate Under nitrogen, a solution of the alcohol of Example 1 (15.0 g, 0.0576 mop and pyridine (15 mL, 0.18 mot) in methylene chloride (60 mL) was cooled to -40°C in a dry ice/isopropanol bath. With stirring, a solution of sulfuryl chloride (16.0 g, 0.118 moD in mekhylene chloride (10 mL) was added gradually (approx, 50 minutes) so that the temperature did not exceed -25°C.
1 0 The ice bath was removed as soon as the addition was complete and the reaction mixture stirred for an additional 2 h. During this time the light yellow precipitate became a clumpy brown solid. Solvent was removed In vucuo to yield a sticky, brown residue. The residue was dissolved in 100 mL
methylene chloride and anhydrous ammonia was bubbled through the 1 5 mixture overnight at ambient temperature. The dark reaction mixture was concentrated in vacuo to give 47.7 g of the title compound as a black residue.
The crude product was found to be 15.10% pure by GLC giving a corrected yield of 36.83%.
2 0 Example 7 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except acetonitrile was used instead of methylene chloride. The title compound was 2 5 isolated as a black residue (45.77 g). The crude product was found to be 25.8%
pure by GLC giving a corrected yield of 60.40%.
Example 8 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-f3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except ether was used instead of methylene chloride in the first step. The title compound was isolated as a black residue (42.84 g). The crude product was found to be 14.8%
pure by GLC giving a corrected yield of 32.43%.
'1 4 ~~~~~a~
Example 9 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-~-D-fructopyranose sulfamate The reaction was carried out the same as in Example 6 except ether was used instead of solvent I (methylene chloride) and acetonitrile was used instead of methylene chloride for solvent 2 (see Table I). A black residue (43.82 g) was obtained on work-up. The crude product was found to be 18.70%
pure by GLC giving a corrected yield of 41.91 %.
Example 10 - (Comparative Example) Preparation of 2,3:4,5-bis-O-(1-methylethylidene)-(3-D-fructopyranose sulfamate The reaction was carried out the same as in Example 8 except that the 1 5 chlorosulfate/methylene chloride solution was placed in a pear shaped pressure bottle and cooled in a dry iee/isopropanol bath. Anhydrous ammonia was bubbled through the mixture for approximately 30~minutes;
then the bottle was tightly stoppered and allowed to slowly warm to room temperature overnight. The bottle was cooled back down before opening and 2 0 the mixture concentrated in vacuo to give 38.51 g of the title compound as a brown tar. The crude product was found to be only 0.55% pure by GLC giving a corrected yield of 1.08%.
Example 11 - (Comparative Example) Preparation of 25 (1-methylcyclohexyl)methane sulfamate Under nitrogen, a solution of (1-methylcyclohexyl)methanol (7.4 g, 0.057 mol) and pyridine (15 mL, 0.179 mol) in methylene chloride (100 mL) was cooled to -10°C in a ice/methanol bath. With stirring, a solution of 3 0 sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (20 mL) was added gradually (approx. 1.0 h) so that the temperature did not exceed -5°C.
The ice bath was removed and the light yellow solution allowed to slowly warm to room temperature over a 2.0 h period. Solvent was removed in vacuo and the resulting yellow slush was slurried in acetonitrile (140 mL). Anhydrous 3 5 ammonia was bubbled through the mixture for 4.0 h. The mixture was filtered, washed with fresh acetonitrile, and concentrated in vacuo to give the ,5 title compound (7.12 g) as a dark oil. The crude product was found to be only 2.24% pure by GLC giving a corrected yield of 1.34%.
Example 12 - (Comparative Example) Preparation of (1-methylcyclohexyl)methane~ sulfamate The reaction was carried out the same as that in Example 11 except diethylether was used for methylene chloride as solvent 1. (see Table 2). No 1 0 product was isolated based on GLC analysis.
Example 13 - (Comparative Example) Preparation of (1-methylcyclohexyl)methane sulfamate 1 5 The reaction was carried out the same as that in Example 11 except methylene chloride was used instead of acetonitrile as solvent 2 (see Table 2).
A product (9.85 g) was isolated as a dark oil. The crude product was found to be 29.1 % pure by GLC giving a corrected yield of 23.97%.
2 0 Example 14 - Preparation of (1-methylcyclohexyl)methane sulfamate Under argon, sulfuryl chloride (18.67 g, 0.138 mol) in toluene (150 mL) was cooled to -50°C in a dry ice/acetone bath. With stirring, a solution of 1-methyl-1-cyclohexane methanol (14.74 g, 0.115 mol) and pyridine (10.94 g, 2 5 0.138 mol) in toluene (150 mL) was added gradually (approx. 40-50 minutes) so that the temperature did not exceed -45°C. The ice bath was removed as soon as the addition was complete. After stirring for an additional 30 minutes water (300 mL) was added and the layers separated. The organic layer was washed with 10% citric acid (2 x 60 mL), water (2 x 100 mL), saturated sodium 3 0 bicarbonate (1 x 100 mL), and saturated sodium chloride (1 x 200 mL), then dried over solid sodium sulfate, filtered, and concentrated in vacuo to give the chlorosulfate (23.53 g, 90.6% yield) as a brownish yellow oil. The oil was dissolved in tetrahydrofuran (300 mL) and the solution added to a 1.0 L
autoclave (with glass liner). The autoclave was pressurized with anhydrous 3 5 ammonia to 28 psi and stirred (290 rpm) at ambient temperature for 16 h. A
mild exotherm was noticed after I.0 h (22 - 35°C). The autoclave was ~0'~8~~.~
depressurized by venting to the air. The mixture was filtered and the solvent removed in vacuo to give 20.41 g of the title compound as a yellow oil. The product was found to be 95.0% pure by GLC giving a corrected yield of 81.33%.
A comparison of the examples of the present invention (Exs. 3-5 and 14) versus those comparative examples of the prior art (Exs. 6-13) in Tables 1 and 2 evidences the advantages of the use o:f the particularly selected solvents in the process of the present invention to produce surprisingly superior 1 0 results over the prior art processes. A direct comparison of Ex. 4 of the invention utilizing the preferred solvents of the invention, e.g. toluene and TI-1F versus comparitive Exs. 6-9 in Table 1 shows a yield improvement of at least 40% and a significant purity improvement for the final product 2,3:4,5-bis-O-(1-methylethylidene)-ø-D-fructopyranose sulfamate . Analagous 1 5 process result improvements are illustrated in Table 2 for the preparation of (I-methylcyclohexyl)methane sulfamate The scope of the present invention is not limited by the description, examples and suggested uses described herein and modifications can be made 2 0 without departing from the spirit of the invention. For example, other sulfamates may be produced utilizing the process of the invention beyond those exemplefied herein.
Applications of the process and methods of the present invention can 2 5 be accomplished by any synthetic method and technique as is presently or prospectively known to those skilled in the chemical and pharmaceutical process arts. Thus it is intended that the present invention cover any modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.
Claims (28)
1. A two step process for synthesizing sulfamates of the formula I:
wherein X is CH2 or oxygen;
R1 is hydrogen or C1-C4 alkyl; and R2, R3, R4 and R5 are independently hydrogen or alkyl, and, when X is oxygen, any of R2 and R3, or R4 and R5, together, may be a methylenedioxy group of the formula (N):
wherein R6 and R7 are the same or different and are hydrogen, alkyl or are alkyl joined together to form a cyclopentyl or cyclohexyl ring, with the proviso that R6 and R7 may not both be H at the same time;
the process comprising in a first step, reacting an alcohol of the formula RCH2OH, wherein R is a moiety of the formula II:
with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent slected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran, to form a compound of the formula III:
RCH2OSO2Cl; and in a second step reacting the compound of formula III
with an amine of the formula R1NH2 in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and lower alkanol to produce the sulfamate of formula I.
wherein X is CH2 or oxygen;
R1 is hydrogen or C1-C4 alkyl; and R2, R3, R4 and R5 are independently hydrogen or alkyl, and, when X is oxygen, any of R2 and R3, or R4 and R5, together, may be a methylenedioxy group of the formula (N):
wherein R6 and R7 are the same or different and are hydrogen, alkyl or are alkyl joined together to form a cyclopentyl or cyclohexyl ring, with the proviso that R6 and R7 may not both be H at the same time;
the process comprising in a first step, reacting an alcohol of the formula RCH2OH, wherein R is a moiety of the formula II:
with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent slected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran, to form a compound of the formula III:
RCH2OSO2Cl; and in a second step reacting the compound of formula III
with an amine of the formula R1NH2 in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and lower alkanol to produce the sulfamate of formula I.
2. The process of claim 1, wherein in the first step the reaction of the compound of formula RCH2OH and sulfuryl chloride is carried out in toluene.
3. The process of claim 1, wherein in the second step the reaction of the compound of formula III with an amine of the formula R1NH2 is carried out in tetrahydrofuran.
4. The process of claim 1, wherein in the first step the reaction of the compound of formula RCH2OH and sulfuryl chloride is carried out in toluene and in the second step the reaction of the compound of formula III with an amine of the formula R1NH2 is carried out in tetrahydrofuran.
5. The process of claim 1, wherein in the first step the tertiary or heterocyclic amine base is selected from the group consisting of pyridine, pyridine derivatives and triethylamine.
6. The process of claim 5, wherein the amine base is pyridine.
7. The process of claim 4, wherein the tertiary or heterocyclic amine base is selected from the group consisting of pyridine, pyridine derivatives and triethylamine.
8 The process of claim 4, wherein the amine base is pyridine.
9. The process of claim 1, wherein in the first step the reaction of the compound of the formula RCH2OH with sulfuryl chloride is carried out at a temperature of about -78°C to 40°C.
10. The process of claim 9, wherein the reaction is carried out at a temperature of from -10°C to 5°C.
11. The process of claim 1, wherein in the second step the reaction of the compound of the formula III with an amine of the formula R1NH2 is carried out at a temperature of about -50°C to 50°C.
12. The process of claim 11, wherein the temperature is of about 15°C
to 20°C.
to 20°C.
13. The process of claim 1, further comprising the step of recrystallizing the compound of formula I.
14. The process of claim 13, wherein the recrystallization step is carried out using a recrystallization medium selected from either of alcohol and water, or ethylacetate/hexane.
15. The process of claim 1, wherein said sulfamate is 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfamate.
16. The process of claim 1, wherein said sulfamate is 2,3:4,5-bis-O-(1-methylethylidene)-.beta.-L-fructopyranose sulfamate.
17. The process of claim 1, wherein said sulfamate is (1-methylcyclohexyl)methane sulfamate.
18. The process of claim 1, wherein in the second step the reaction of the compound of formula III with an amine of formula R1NH2 is carried out at a pressure of from about one atmosphere to 50 psi.
19. The process of claim 18, wherein the pressure is about 30 psi.
20. The process of claim 18, wherein the pressure is about 22 psi.
21. The process of claim 1, wherein in the second step the reaction of the compound of the formula III with an amine of the formula R1NH2 is carried out in a presaturated solution of the amine.
22 The process of claim 21, wherein the amine of the formula R1NH2 is ammonia.
23. The process of claim 1, wherein in the second step the reaction of the compound of formula III with an amine of the formula R1NH2 is carried out by bubbling the amine into a solution containing the compound of formula III.
24. The process of claim 23 wherein the amine of the formula R1NH2 is ammonia.
25. The process of claim 1 wherein said compound of formula III is 2,3:4,5 bis-O-(1-methylethylidene)-.beta.-D-fructopyranose sulfonyl chloride.
26. The process of claim 1 wherein said compound of formula III is 2,3:4,5 bis-O-(1-methylethylidene)-.beta.-L-fructopyranose sulfonyl chloride.
27. The process of claim 21 wherein the amine of the formula R1NH2 is NH4OH.
28. A two step process for synthesizing sulfamates of the formula VII:
comprising in a first step reacting a compound of formula V:
with sulfuryl chloride in a toluene solvent in the presence of pyridine at a temperature of about -20°C to 5°C to produce a compound of the formula VI
and thereafter in a second step reacting the compound of formula VI
with gaseous ammonia at a pressure of about 14 to 30 psi in tetrahydrofuran at a temperature of about 15 to 18°C to produce the compound of formula VII, and thereafter recrystallizing the compound of formula VII from an ethanol and water solvent.
comprising in a first step reacting a compound of formula V:
with sulfuryl chloride in a toluene solvent in the presence of pyridine at a temperature of about -20°C to 5°C to produce a compound of the formula VI
and thereafter in a second step reacting the compound of formula VI
with gaseous ammonia at a pressure of about 14 to 30 psi in tetrahydrofuran at a temperature of about 15 to 18°C to produce the compound of formula VII, and thereafter recrystallizing the compound of formula VII from an ethanol and water solvent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76272091A | 1991-09-19 | 1991-09-19 | |
| US762,720 | 1991-09-19 | ||
| US92626992A | 1992-08-05 | 1992-08-05 | |
| US926,269 | 1992-08-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2078519A1 CA2078519A1 (en) | 1993-03-20 |
| CA2078519C true CA2078519C (en) | 2003-09-16 |
Family
ID=27117178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078519A Expired - Lifetime CA2078519C (en) | 1991-09-19 | 1992-09-17 | Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3:4,5-bis-0-(1-methylethylidene)-beta-d-fructopyranose and (1-methylcyclohexyl)methanol |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US5387700A (en) |
| EP (1) | EP0533483B1 (en) |
| JP (1) | JP3174410B2 (en) |
| KR (1) | KR100229180B1 (en) |
| CN (1) | CN1035820C (en) |
| AT (1) | ATE163937T1 (en) |
| AU (1) | AU651244B2 (en) |
| CA (1) | CA2078519C (en) |
| DE (1) | DE69224691T2 (en) |
| DK (1) | DK0533483T3 (en) |
| EG (1) | EG20164A (en) |
| ES (1) | ES2114917T3 (en) |
| FI (1) | FI107731B (en) |
| GR (1) | GR3026618T3 (en) |
| HU (1) | HU212634B (en) |
| IL (1) | IL103172A (en) |
| MX (1) | MX9205305A (en) |
| MY (1) | MY113564A (en) |
| NO (1) | NO179284C (en) |
| NZ (1) | NZ244409A (en) |
| PH (1) | PH31291A (en) |
| TW (1) | TW217413B (en) |
| ZW (1) | ZW14792A1 (en) |
Families Citing this family (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3250777B2 (en) * | 1995-02-13 | 2002-01-28 | セントラル硝子株式会社 | Imides, salts thereof and methods for producing them |
| UA65607C2 (en) * | 1998-03-04 | 2004-04-15 | Орто-Макнейл Фармацевтикал, Інк. | Pharmaceutical composition (variants) and process for its preparation |
| AU779823B2 (en) * | 1999-02-17 | 2005-02-10 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating essential tremor |
| US6420369B1 (en) | 1999-05-24 | 2002-07-16 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating dementia |
| MY126897A (en) * | 2000-07-07 | 2006-10-31 | Ortho Mcneil Pharm Inc | Anticonvulsant derivatives useful for preventing the development of type ii diabetes mellitus and syndrome x |
| US6627653B2 (en) | 2000-08-02 | 2003-09-30 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful for the treatment of depression |
| JP2004518718A (en) * | 2000-10-30 | 2004-06-24 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Combination therapy comprising antidiabetic and anticonvulsants |
| UA78211C2 (en) * | 2001-07-09 | 2007-03-15 | Ortho Mcneil Pharm Inc | Salts of fructopyranose derivatives as anticonvulsant |
| US7041650B2 (en) * | 2001-07-09 | 2006-05-09 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivative salts |
| MXPA04004380A (en) * | 2001-11-06 | 2005-06-08 | Johnson & Johnson | Treatment and prevention of paresthesia comprising co-therapy with anticonvulsant derivatives and potassium. |
| RU2004126093A (en) * | 2002-02-26 | 2005-04-10 | Орто-Макнейл Фармасьютикал, Инк. (Us) | COMBINED THERAPY FOR TREATMENT OF MIGRAINES, INCLUDING THE USE OF ANTIVASOUS DERIVATIVE DERIVATIVES AND MIGRAIN AGENTS |
| CA2477923C (en) | 2002-03-01 | 2021-02-23 | University Of South Florida | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
| US7060725B2 (en) | 2002-05-13 | 2006-06-13 | Janssen Pharmaceutica N.V. | Substituted sulfamate anticonvulsant derivatives |
| US20050175697A1 (en) * | 2003-12-29 | 2005-08-11 | David Edgren | Novel drug compositions and dosage forms of topiramate |
| AR039744A1 (en) * | 2002-06-26 | 2005-03-09 | Alza Corp | METHODS AND DOSAGE FORMS TO INCREASE THE SOLUBILITY OF PHARMACOS COMPOSITIONS FOR CONTROLLED ADMINISTRATION |
| CA2494233A1 (en) * | 2002-07-29 | 2004-02-05 | Alza Corporation | Formulations and dosage forms for controlled delivery of topiramate |
| US7196209B2 (en) * | 2002-10-31 | 2007-03-27 | Ortho-Mcneil Pharmaceutical, Inc. | Continuous process for the preparation of fructopyranose sulfamate derivatives |
| UA80450C2 (en) * | 2002-10-31 | 2007-09-25 | Ortho Mcneil Pharm Inc | Continuous process for the preparation of fructopyranose sulfamate derivatives |
| UA81657C2 (en) * | 2003-03-04 | 2008-01-25 | Орто-Макнейл Фармасьютикел, Инк. | Normal;heading 1;heading 2;PROCESS FOR THE PREPARATION OF ANTICONVULSANT DERIVATIVES OF TOPIRAMATE |
| WO2004108732A1 (en) * | 2003-05-12 | 2004-12-16 | Sun Pharmaceutical Industries Limited | PROCESS FOR THE PREPARATION OF 2,3:4,5-BIS-O(1-METHYLETHYLIDENE)-ß-D-FRUCTOPYRANOSE SULFAMATE |
| CA2534920A1 (en) * | 2003-08-06 | 2005-02-24 | Alza Corporation | Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation |
| JP2007503389A (en) * | 2003-08-22 | 2007-02-22 | アルザ・コーポレーシヨン | Staged delivery of topiramate over long periods of time |
| AU2004268661A1 (en) * | 2003-09-02 | 2005-03-10 | Alza Corporation | Novel drug compositions and dosage forms of topiramate |
| CN1905857A (en) * | 2003-11-14 | 2007-01-31 | 阿尔扎公司 | Controlled release of topiramate in liquid dosage forms |
| KR20050062976A (en) * | 2003-12-19 | 2005-06-28 | 일동제약주식회사 | A new improved preparation method of 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate |
| EP1701706A2 (en) * | 2003-12-29 | 2006-09-20 | Alza Corporation | Novel drug compositions and dosage forms |
| US20050175696A1 (en) * | 2003-12-29 | 2005-08-11 | David Edgren | Drug granule coatings that impart smear resistance during mechanical compression |
| US20050203287A1 (en) * | 2004-03-11 | 2005-09-15 | Chandrasekhar Batchu | Process for the preparation of sulfamate derivatives |
| MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
| AR049646A1 (en) * | 2004-06-16 | 2006-08-23 | Janssen Pharmaceutica Nv | USEFUL SULFAMATE AND SULFAMIDE DERIVATIVES FOR THE TREATMENT OF EPILEPSY AND RELATED DISORDERS |
| US20060047001A1 (en) * | 2004-08-24 | 2006-03-02 | Parker Michael H | Novel benzo-fused heteroaryl sulfamide derivatives useful as anticonvulsant agents |
| BRPI0516562A (en) * | 2004-10-05 | 2008-10-28 | Fallbrook Technologies Inc | continuously variable transmission |
| WO2006127184A1 (en) * | 2005-05-20 | 2006-11-30 | Janssen Pharmaceutica N.V. | Process for preparation of sulfamide derivatives |
| JP2008542237A (en) * | 2005-05-25 | 2008-11-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Topiramate pediatric formulation |
| US20070155823A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents |
| US8497298B2 (en) * | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
| US20070155827A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression |
| AR058389A1 (en) * | 2005-12-19 | 2008-01-30 | Janssen Pharmaceutica Nv | USE OF SULFAMIDE BENZO-FUSED HETEROCICLIC DERIVATIVES FOR THE TREATMENT OF OBESITY |
| US8937096B2 (en) * | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
| US8691867B2 (en) * | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
| US8716231B2 (en) * | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
| US20070191459A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of Benzo-Heteroaryl Sulfamide Derivatives for Lowering Lipids and Lowering Blood Glucose Levels |
| US20070191474A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of migraine |
| US20070191453A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-heteroaryl sulfamide derivatives for the treatment of substance abuse and addiction |
| US20070191449A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of Benzo-Heteroaryl Sulfamide Derivatives for the Treatment of Depression |
| US20070191461A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-heteroaryl sulfamide derivatives for the treatment of migraine |
| WO2007099388A1 (en) * | 2006-03-01 | 2007-09-07 | Glade Organics Private Limited | An improved process for the manufacture of topiramate |
| WO2007108009A1 (en) * | 2006-03-17 | 2007-09-27 | Alembic Limited | A process for purification of topiramate |
| AU2007253814A1 (en) * | 2006-05-19 | 2007-11-29 | Janssen Pharmaceutica N.V. | Co-therapy for the treatment of epilepsy |
| JP5424571B2 (en) * | 2007-04-12 | 2014-02-26 | 協和発酵キリン株式会社 | Topiramate-containing solid preparation |
| EP2573424A3 (en) * | 2007-04-24 | 2017-07-26 | Fallbrook Intellectual Property Company LLC | Electric traction drives |
| CN101450951B (en) * | 2007-11-30 | 2012-10-10 | 重庆凯林制药有限公司 | Method for producing topiramate |
| US20090247617A1 (en) * | 2008-03-26 | 2009-10-01 | Abdel-Magid Ahmed F | Process for the preparation of benzo-fused heteroaryl sulfamates |
| US20090247616A1 (en) * | 2008-03-26 | 2009-10-01 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of anxiety |
| PE20110060A1 (en) | 2008-06-23 | 2011-01-31 | Janssen Pharmaceutica Nv | CRYSTALLINE FORM OF (2S) - (-) - N- (6-CHLORO-2,3-DIHYDRO-BENZO [1,4] DIOXIN-2-ILMETHYL) -SULFAMIDE |
| US8815939B2 (en) * | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
| JP5643844B2 (en) * | 2010-02-05 | 2014-12-17 | サイノファーム タイワン リミテッド | Topiramate manufacturing method |
| CN102936268A (en) * | 2012-11-13 | 2013-02-20 | 江苏吉贝尔药业有限公司 | Process for preparing topiramate midbody acetonylidene |
| CN106397502A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Synthesis technology of topiramate |
| CN108341844A (en) * | 2018-04-25 | 2018-07-31 | 广州小桔生物科技有限公司 | A kind of preparation method of high-purity Topiramate |
| CN110655541A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate crystal form |
| CN110655542A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate |
| EP3883546A1 (en) | 2018-11-21 | 2021-09-29 | Rosemont Pharmaceuticals Ltd | Oral topiramate suspension formulations with extended shelf stability and enhanced bioavailability |
| CN114350340B (en) * | 2022-01-13 | 2023-01-17 | 陕西科技大学 | Permeation enhancer for fracturing and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4513006A (en) * | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
| US4582916A (en) * | 1983-09-26 | 1986-04-15 | Mcneilab, Inc. | Chlorosulfate and azidosulfate esters of tetrahydro-2H-pyran-2-yl-methanol |
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1992
- 1992-09-15 IL IL10317292A patent/IL103172A/en not_active IP Right Cessation
- 1992-09-15 AU AU24518/92A patent/AU651244B2/en not_active Expired
- 1992-09-17 EG EG54692A patent/EG20164A/en active
- 1992-09-17 MY MYPI92001667A patent/MY113564A/en unknown
- 1992-09-17 CA CA002078519A patent/CA2078519C/en not_active Expired - Lifetime
- 1992-09-18 ZW ZW14792A patent/ZW14792A1/en unknown
- 1992-09-18 AT AT92308509T patent/ATE163937T1/en active
- 1992-09-18 KR KR1019920017043A patent/KR100229180B1/en not_active IP Right Cessation
- 1992-09-18 JP JP27351092A patent/JP3174410B2/en not_active Expired - Lifetime
- 1992-09-18 ES ES92308509T patent/ES2114917T3/en not_active Expired - Lifetime
- 1992-09-18 DK DK92308509T patent/DK0533483T3/en active
- 1992-09-18 EP EP92308509A patent/EP0533483B1/en not_active Expired - Lifetime
- 1992-09-18 PH PH44955A patent/PH31291A/en unknown
- 1992-09-18 HU HU9202974A patent/HU212634B/en unknown
- 1992-09-18 NZ NZ244409A patent/NZ244409A/en not_active IP Right Cessation
- 1992-09-18 MX MX9205305A patent/MX9205305A/en unknown
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1993
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